Dr Olson on the Potential Benefit of Lifileucel in Relapsed/Refractory Metastatic Melanoma

Daniel Olson, MD, assistant professor, medicine, the University of Chicago Medical Center, UChicago Medicine, discusses the benefit associated with lifileucel (Amtagvi) in patients with unresectable or metastatic melanoma, highlighting patients likely to derive the most benefit from this treatment approach.

 for the treatment of adult patients with previously treated unresectable or metastatic melanoma was granted in February 2024, Olson begins, saying that this regulatory decision represents a significant advancement in the field of melanoma management, offering a valuable treatment option for patients who have exhausted current standard treatments. Although lifileucel is not suitable for all patients due to potential adverse effects (AEs) and safety considerations, this therapy holds promise for younger patients with melanoma or older patients who remain in good health but lack effective standard therapies, he explains.

Research on tumor-infiltrating lymphocytes (TILs), including lifileucel, has demonstrated encouraging outcomes, underscoring the therapeutic potential of TILs and reaffirming findings dating back to the 1990s that suggest the curative capabilities of these agents, Olson expands. The commercial availability of lifileucel provides oncologists with another valuable tool to offer patients, particularly those with melanoma subtypes that exhibit resistance to standard immunotherapies, such as mucosal melanoma, he reports.

Notably, mucosal melanoma, which has had limited responsiveness to standard immunotherapy, may benefit from TIL-based therapies, according to Olson. Lifileucel is recommended for patients who have progressed on a prior PD-1 inhibitor and, if they have 

 V600–positive disease, a BRAF inhibitor with or without a MEK inhibitor, he explains. However, oncologists may need to consider the timing of treatment initiation, especially for patients with BRAF mutations, prompting discussions on whether to administer the therapy earlier in the treatment course or after targeted treatment options have been exhausted, Olson says.

Ultimately, the decision on when to incorporate lifileucel in a patient’s melanoma treatment sequencing will be tailored to each patient's circumstances, balancing the potential benefits of the treatment with considerations about overall health and treatment history, he concludes.

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Daniel Olson, MD, discusses the benefit associated with lifileucel in patients with unresectable or metastatic melanoma.

Dr Olson on Toxicities Associated With Lifileucel and IL-2 in Melanoma

Daniel Olson, MD, assistant professor, medicine, the University of Chicago Medical Center, UChicago Medicine, discusses toxicities associated with lifileucel (Amtagvi) and interleukin-2 (IL-2)in patients with unresectable or metastatic melanoma.

lifileucel was granted FDA accelerated approval

 for the treatment of adult patients with previously treated unresectable or metastatic melanoma. The adverse effects (AEs) associated with the lifileucel-based regimen predominantly stem not from lifileucel itself but from the conditioning chemotherapy and IL-2 component, Olson begins. Lifileucel, which comprises a patient's own T cells, does not inherently induce significant toxicity, as these cells are sensitized to self-antigens and typically do not provoke cross-reactions or cytokine release, contrasting with engineered cell therapies such as CAR T cells and T-cell receptor T cells. Consequently, the personalized nature of lifileucel immunotherapy minimizes off-target or off-tumor effects, he reports.

Lymphodepleting chemotherapy commonly leads to cytopenias due to a decline in blood cell counts, and IL-2 therapy is associated with its own set of toxicities, including fever, rash, hypotension, and thrombocytopenia, he reports. Despite prior use of IL-2 in higher doses for conditions such as melanoma and renal cell cancer, lifileucel therapy employs IL-2 primarily to activate patient T cells rather than to maximize dosing, aiming to mitigate serious AEs, such as vascular leak syndrome, Olson elucidates.

Although patients may experience transient AEs during lifileucel treatment, the therapy's one-time administration offers the advantage of temporary toxicity, he continues. Typically, high-grade toxicities resolve within 2 to 3 weeks post-treatment, allowing a return to baseline health status as blood counts recover, according to Olson. Patient selection for lifileucel therapy hinges significantly on patients’ ability to tolerate IL-2, given its intense nature and potential exacerbation of underlying comorbidities, such as cardiac, pulmonary, or renal issues, Olson says.

Consequently, careful consideration of patient health status, including cardiac stress testing and overall fitness, is paramount to ensure appropriate candidacy for lifileucel therapy, Olson emphasizes. Although temporary, lifileucel-associated AEs necessitate thorough evaluation of patient suitability and close monitoring to optimize treatment outcomes, he concludes.

Daniel Olson, MD, discusses toxicities associated with lifileucel and IL-2 in patients with unresectable or metastatic melanoma.

Dr Olson on the FDA Approval of Lifileucel for Advanced Melanoma

Daniel Olson, MD, assistant professor, medicine, the University of Chicago Medical Center, discusses the FDA approval of lifileucel (Amtagvi), the first cellular and tumor infiltrating lymphocyte (TIL) therapy product to be approved by the FDA for patients with unresectable or metastatic melanoma whose disease has been previously treated with a PD-1 inhibitor, as well as a BRAF inhibitor with or without a MEK inhibitor for 

This agent was approved on February 16, 2024

, based on data from cohorts 2 and 4 of the phase 2 C-144-01 trial (NCT02360579). These data showed that in patients who were treated with the recommended dose of lifileucel (n = 73), the objective response rate was 31.5% (95% CI, 21.1%-43.4%); this included a complete response rate of 4.1% and a partial response rate of 27.4%. 

Lifileucel stands out as the first TIL therapy to gain FDA approval, and has a distinct mechanism of action compared with those of other treatments, Olson begins. Unlike typical immunotherapies, lifileucel harnesses the patients’ own T cells extracted from tumors, which are then processed, expanded, and activated externally, he states. Some tumor-derived T cells are anticipated to exhibit reactivity toward the tumor, Olson explains. Curiously, the specific targets within the tumor remain unidentified; however, the T-cell selection process based on tumor proximity enhances the likelihood of obtaining reactive T cells. Upon expansion and reintroduction into the patient, these T cells may target the tumor, he adds.

The lifileucel manufacturing process spans several weeks, during which T cells are isolated, expanded, and activated, Olson continues. Following conditioning chemotherapy, the patient's activated T cells are reintroduced and further activated in vivo with interleukin 2. Ideally, certain subsets of these cells will confront the tumor, migrating back to the disease site and overcoming resistance, he states. Although the precise mechanisms by which these T cells operate to overcome immunotherapy resistance are not fully understood, clinical evidence indicates that even patients unresponsive to previous immunotherapies can derive substantial and enduring benefits from lifileucel, he concludes.

Daniel Olson, MD, discusses the FDA approval of lifileucel for patients with advanced melanoma whose disease has been previously treated.

Daniel Olson, MD

Articles

Dr Olson on the Potential Benefit of Lifileucel in Relapsed/Refractory Metastatic Melanoma

Dr Olson on Toxicities Associated With Lifileucel and IL-2 in Melanoma

Dr Olson on the FDA Approval of Lifileucel for Advanced Melanoma